Electric pulse applicator using pairs of needle electrodes for the treatment of biological tissue

ABSTRACT

An electric pulse applicator for the treatment of biological tissue applies an electric field to the cells of biological tissue to modify the properties of their membranes. The electric pulse applicator includes electrodes and a pulse generator. The electrodes comprise at least three needles which are introduced into the tissue to be treated and which define a treatment volume. The needles are formed into pairs and a selector switch directs successive pulses produced by the pulse generator to each different pair of needles.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a device for applying electric pulses for thetreatment of biological tissue. It is particularly intended for theimplementation of electrochemotherapy.

2. Discussion of Background

Electrochemotherapy is a new therapeutic method that has been developedin particular for the treatment of cancers.

Indeed, it has been found that a certain number of active substanceshave difficulty in traversing the membrane of the cells that the areintended for.

To overcome this difficulty, it is often necessary to increase the dosesof the substances provided, this often being difficult and nearly alwayshaving unwanted side effects.

It has recently been shown that the permeability of a cell's plasmamembrane can be increased by applying electric pulses to the cell.

Electrochemotherapy takes advantage of this possibility by combining theinjection of an active substance with the application of short, intenseelectric pulses. The penetration of the active substance into the cellssubjected to the electric field is thus facilitated. Electrochemotherapyhas, for example, been used to treat tumors using bleomycin. Theantitumor effects of bleomycin combined with the electric pulses can bepotentiated by injections of immunostimulants such as interleukines, forexample interleukine-2, or injections of medicamentous compositions suchas syngenic, allogenic or xenogenic cells that secrete interleukines,for example interleukine-2. The injection of these substances orcompositions is especially effective if it is done locally at the levelof the tumor, treated beforehand by electrochemotherapy.

The electric fields required to implement electrochemotherapy have, todate, been obtained by applying pulses between two external electrodesplaced, as far as possible, on either side of the tumor to be treated.

The electrical contact of these electrodes with the skin is ensured by aconductive gel.

Such a technique is described, for example, in the "Compte-Rendu deI'Academie des Sciences de Paris" t.313, series III, pages 613-618,1991: "L'electrochimiotherapie, un nouveau traitement antitumor: premieressai clinique" (Electrochemotherapy, a new antitumor treatment: firstclinical trial) Lluis M. MIR et al.

The electrodes used to date for applying electric pulses cannotuniformly distribute the electric fields produced throughout the wholevolume to be treated, and require, for the chemotherapeutic part, thatthe antitumor medicamentous product be injected into the patient's wholebody.

SUMMARY OF THE INVENTION

The object of this invention is an applicator which improves thedistribution and control of electric fields produced forelectrochemotherapy.

Another object of the invention is to propose an electric pulseapplicator whose use avoids or limits the side effects produced.

A further object of the invention is to propose an electric pulseapplicator for electrochemotherapy that may be used several timeswithout causing unwanted lesions of healthy tissue close to the tumor,for example of the skin.

A further object of the invention is to propose a compact, sterilizable,autoclavable device capable of withstanding high voltage.

With this object in view, the invention therefore relates to an electricpulse applicator for the treatment of biological tissue allowing anelectric field to be applied to cells of biological tissue so as tomodify the properties of their membrane. This applicator compriseselectrodes and a pulse generator.

According to the invention, the electrodes comprise at least threeneedles which are intended to be introduced into the tissue to betreated and to define a treatment volume, said needles forming in twospairs of needles, and a needle selector switch which sends the pulsesproduced by the pulse generator successively onto the different pairs ofneedles.

According to different preferred embodiments, the electric pulseapplicator for the treatment of biological tissue of the inventioncomprises the following characteristics, taken alone or in anytechnically feasible combination:

- the needles of the electrodes are fixed onto a needle applicator in aninterchangeable way;

- the needles each comprise a base and a stem terminated by a point, thebase ensuring the fixing of the needle onto the needle holder, the pointensuring the penetration of the needle into the tissue, one or moreportions of the stem being surrounded by an insulating sleeve;

- one portion of the insulating sleeve of the needles is intended toremain implanted in the tissue;

- the electrodes comprise a central needle and six peripheral needles,regularly distributed on a circle centered on the central needle;

- the voltage of the applied pulses is proportional to the distance,separating the two needles between which it is applied;

- each needle is separated from its neighbors by a distance of 4 to 10mm, and preferably 6.5 mm.

- each electric pulse is a rectangular pulse of amplitude 100 to 1500 Vand pulse length 10 to 200 μs;

- the needles of the electrodes are hollow and allow the activesubstance to be injected locally into the treatment volume;

- the needle holder carries a syringe associated with each needle, saidsyringe being formed of a body and a piston;

- the needle selector switch comprises two relays associated with eachneedle, said selector switch being able to connect the needle to thepositive terminal or negative terminal of the pulse generator;

- the applicator comprises a control unit which can produce a givensequence of electric pulses as determined by the operator, following theinjection of substance.

The invention will be better understood from the following detaileddescription of a particular embodiment of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic drawing of the general electric circuit of theinvention.

FIG. 2 is a cross-sectional view of a needle.

FIG. 3 is a partial cross-sectional view of a needle holder.

FIG. 4 is a cross-sectional view of the fixing of a needle onto theneedle holder.

FIG. 5 is an above view of the upper plate of the needle holder.

FIG. 6 is an above view of the bottom of the needle holder.

FIG. 7 is an above view of the insulating washer of the needle holder.

FIG. 8 is a cross-sectional view of the needle holder showing theelectric link of the needle with the pulse generator.

FIG. 9 is a partial cross-sectional view of a syringe with a conductingbody in the injecting state.

FIG. 10 is a partial cross-sectional view of a syringe with a conductingbody in the electric field application state.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Since the needles are all structurally identical and associated with thesame elements, each of these elements is designated by a singlereference irrespective of the needle to which it is intended. Thisreference may possibly be followed by an index corresponding to thereference number of the needle.

The electric pulse applicator for the electrochemotherapy biologicaltissue is intended to apply a variable electric field to cells locatedbetween a pair of needles 1, 2 . . . n.

To achieve this, it comprises a pulse generator 10, a selector switch 11and a control unit 12. Pulse generator 10 comprises a high voltage powersupply 13 which is connected to the mains supply by a mains cord 14, andto the selector switch via a switch 15 connected to the, generator'spositive output, a capacitor 17 being connected in parallel across itspositive output 16 and negative output 18.

Each electrode 1, 2, . . . n, can be connected either to the positivepole 16 of the high voltage power supply, or to its negative pole 18 bymeans of two relays 19₁, 20₁, 19₂, 20₂, . . . 19_(n), 20_(n) belongingto selector switch 11.

Control unit 12 controls the high tension power supply 13, switch 15 andchangeover switch 11 according to the instructions it receives from anoperator or via a program.

The electric pulse applicator is thus able to apply previouslydetermined pulse cycles between needles 1, 2 . . . n in twos and in allpossible combinations.

These cycles can be determined by any means, particularly experimental,in order to provide best possible results.

Preferably, relays 19₁, 20₁. . . 19_(n), 20_(n) are formed by a barrelay or REED bulb relay, the excitation for which is produced either byphysical displacement of a small magnet whose position is slaved, or bya conventional command using a coil. This displacement is produced by aconventional position slaving system ensured by a coil.

Thanks to this arrangement, selector switch 11 can be made very compact.

For example, by closing relay 19₁ and relay 20_(n), it is possible whenswitch 15 is closed to send a pulse between electrodes 1 and n,electrode 1 being the positive electrode and electrode n the negativeelectrode.

The electric contact is established with the tissue via the electrodesover all their non-insulated length, the produced field thus extendinginto the depth of the tissue. It is therefore possible to subject cellsto electric fields which would not be accessible, at least not easily,from electrodes simply placed on the surface of the tissue.

Preferably, the pulses applied to each pair of needles are rectangularpulses having an amplitude of 100 to 1500 V and a pulse length of 10 to200 μs. These pulses are spaced, for each pair of needles, by anadjustable interval in the range 0.2 to 2 seconds, and preferably 1second.

For each pair of needles, it is possible, for example, to apply eightsuccessive pulses of the same polarity, or four pulses of a firstpolarity followed later in the cycle by four pulses of the oppositepolarity. In the case of electrodes comprising many needles, for exampleseven as in the embodiment described below, the pulse sequencesconcerning the different pairs of needles can be interleaved. Thus,given the length of each pulse and of the interval which must separatetwo successive pulses applied to a given pair of electrodes, it ispossible to excite the different pairs of electrodes one after anotherwhile respecting these sequences.

The electric fields thus produced can be approximately uniformlydistributed, including in depth, since the needles penetrate into thetissue and define therefore a set of elementary volumes of tissue, eachof these volumes being included between two electrodes of a pair. Bysuccessively applying electric fields to these elementary volumes, gooduniformity of treatment can be obtained over the whole volume ofbiological tissue treated.

Each needle 1, 2 . . . n, comprises a base 30, a head 31, a connector 32comprising a flat surface and a base 33.

Base 33 carries stem 34 which is terminated by a point 35. One or moreparts of stem 34 preferably comprise an insulating sleeve 36, made forexample from PTFE (polytetrafluoroethylene) which provides, wheninserted into tissue, a means of preventing the application of electricpulses to certain zones. In particular, it is often preferable to avoidapplying the electric field to the surface.

In addition, according to a preferred embodiment, the part of thisinsulating sheath 36 in the visinity of the base is removable and can beleft for a certain period of time in the tissue to facilitate use of thepulse applicator on several occasions when creating the same tissuevolume, without any risk of damaging healthy superficial tissue andalso, once the electric treatment has finished (at least provisionally),to continue with injecting one or more substances or medicamentouscompositions (for example immunomodulators, such as interleukine-2 orsecreting cells for example of interleukine-2). A further advantage ofthe catheter thus formed is that its flexibility allows it to be wornfor a prolonged period without physical tissue lesion.

Advantageously, the needles are fixed onto a needle holder 40. Thisneedle holder is, for example, generally circular in section, andcomprises an upper plate 41, a bottom plate 42 and an insulating washer43. Insulating plate 43 rests on bottom plate 42 which is connected tothe upper plate by small columns 44 forming distance sleeves. Thesesmall columns 44 are screwed into bottom plate 42 and receive bolts 45ensuring the fixing of upper plate 41. Inserts 46 are placed in theopenings provided for this purpose in the bottom plate and insulatingplate anti receive heads 31 of the needles. Heads 31 can, for example,be threaded, inserts 46 having a complementary thread. An external tool,not shown, is able to work with the flat surfaces of zone 32 of theneedles, and can for example be used to facilitate the assembly andremoval of needles in inserts 46.

An electrical connection 100 establishes link 46 between insert 46 andselector switch 11 via a wire 101. Advantageously, a seal 47 ensures agood link between needles 1, 2, . . . n, and inserts 46.

Each needle 1, 2 . . . n, is connected to selector switch 11 by means ofthe insert 46 on which is screwed, and is therefore able to be connectedto pulse generator 10.

The upper plate comprises passages 44 for the small columns and passages48 for the electric wires.

The insulating washer comprises passages 44 for the small columns andpassages 49 to ensure its fixing onto the bottom plate.

According to the preferred embodiment, needles 1, 2 . . . n arc hollowand can be used to locally inject a locally active substance.

For this purpose, needles 1, 2 . . . n are hollow and connected by meansof inserts 46 to syringes 50 comprising a body 51 and a piston 52. Upperplate 41 bears against body 51 of the syringes and helps hold them inposition.

This plate 41 comprises passages 53 allowing pistons 52 of syringes 50to move freely.

An external cylinder 54 is advantageously provided and fixed to upperplate 41 on the one hand, and to bottom plate 42 on the other hand. Thisexternal cylinder surrounds the device thus protecting it andfacilitating its handling. This external cylinder 54, on the one hand,bears against bottom plate 42 comprising a shoulder 60 provided for thispurpose, and on the other hand is screwed on upper plate 41 by a screw61 working with a thread 62 made in upper plate 41.

The hollow stem 34 of the needle comprises at least one opening at itsend 35. In order to improve the homogeneous distribution of the injectedsubstance throughout all the volume of the treated tissue, it alsopreferably comprises openings 37, 38 distributed at intermediate levelsover its height. Such a needle is known as "fenestrated".

According to a further embodiment, the body of syringes 51 areconductors, for example, metallic, which makes it possible to simplifythe electric links.

Pistons 52 are actuated by moveable rods 55. Rods 55 are, for example,screwed onto piston 52 and can be unscrewed.

The needles are therefore supplied with electric power via syringebodies 51. Their upper portion forms a female electric contact whichworks with a male plug holder 56 connected to selector switch 11.

Rods 55 are first of all fixed onto pistons 52 to allow the injection tobe performed. They are then removed and the plug holder connected ontosyringe bodies 51. Electrical pulses can now be applied.

FIGS. 5, 6 and 7 show the distribution of the needles and syringes whenseven of them are simultaneous used. One of them 1 is arranged al: thecenter and the other six 2-7 equally distributed on a circle centered onthe first.

Advantageously, derived distributions could be used when a larger numberof needles are used. For example, nineteen needles could be used byplacing the twelve additional needles on a second crown concentric withthe first circle, the radius of the second crown being approximatelydouble that of the first circle. Thirty-seven needles can be distributedby distributing, with respect to the first circle, the eighteenadditional needles uniformly around a third crown concentric with thefirst circle, the radius of the third crown being approximately threetimes that of the first circle, in such a way that all pairs comprisinga given needle and all those surrounding it are equidistant.

If the needles are not equidistant, the voltage of the applied pulse;will depend on the spacing of the pair of needles to which it isintended. This voltage is preferably proportional to the spacing.

The characteristics of the electric pulses can generally be determinedwith a view to a particular protocol. They are not necessaryrectangular.

The electric pulse applicator can therefore be used in the followingway. Syringes 50 are first of all filled with the solution containingthe active substance to be injected.

The device is then placed in position by introducing the needles intothe tissue to be treated.

The active substance is then injected.

After a waiting period determined by experience, control unit 12 istriggered and the electric pulse sequences activated so as to producethe desired intensities of electric field at the heart of the tissuelocated between or in the vicinity of the needles. At the end of theelectric treatment, the needles are withdrawn, the insulating sleevesbeing, if necessary, left in place to allow substances or medicamentouscompositions to be injected at a later time.

Other variations can be envisaged with respect to the above; embodimentwithout leaving the scope of the claims. In particular, the control ofthe generator can be performed from a distance and, for example, from atrigger mounted on the applicator.

Moreover, the shape of the electric pulses could be modified and adaptedaccording to experimental results.

The reference numerals inserted after the characteristic featuresmentioned in the claims are merely intended to facilitate theunderstanding of the latter without limiting at all the range claimed.

We claim:
 1. Electric pulse applicator for the treatment of biologicaltissue allowing an electric field to be applied to cells of biologicaltissue in such a way as to modify properties of their membrane,comprising:electrodes, the electrodes including at least three needlesintended to be introduced into the tissue to be treated and which definea treatment volume, said needles in twos forming pairs of needles; apulse generator sending pulses to the electrodes, the pulse generatorhaving a negative pole and a positive pole; a selector switch connectedto and arranged between the pulse generator and the electrodes, theselector switch being able to connect each needle with either thenegative pole or the positive pole of the pulse generator and therebycan direct the pulses produced by the pulse generator successively ontoall the different pairs of needles; and a control mechanism connected tothe selector switch and pulse generator for controlling the pulsegenerator and the selector switch so as to form any pairs of needlesamong the needles.
 2. The electric pulse applicator of claim 1, whereinthe electrodes comprise a central needle and six peripheral needlesregularly distributed on a circle centered on the central needle.
 3. Theelectric pulse applicator of claim 1, wherein said pulses comprise avoltage which is proportional to a distance separating the two needlesbetween which the voltage is applied.
 4. The electric pulse applicatorof claim 1, further comprising a control unit connected to the selectorswitch.
 5. The electric pulse applicator of claim 1, wherein each needleis separated from its neighbors by a distance of 4 to 10 mm.
 6. Theelectric pulse applicator of claim 5, wherein each needle is separatedfrom its neighbors by a distance of 6.5 mm.
 7. The electric pulseapplicator of claim 1, wherein each needle has and is connected to firstand second relays, each first and second relay forming a portion of theselector switch.
 8. The electric pulse applicator of claim 7, whereinsaid selector switch comprises means for activating each first relay toconnect each needle to the positive terminal of the pulse generator,said selector switch also comprises means for activating each secondrelay to connect each needle to the negative terminal of the pulsegenerator.
 9. The electric pulse applicator of claim 1, wherein theneedles of the electrodes are fixed onto a needle holder in aninterchangeable way.
 10. The electric pulse applicator of claim 9,wherein the needles each comprise a base and a stem terminated by apoint, the base ensuring the fixing of the needle onto the needleholder, the point ensuring the penetration of the needle into thetissue, at least one portion of the stem being surrounded by aninsulating sleeve.
 11. The electric pulse applicator of claim 10,wherein a removable portion of the insulating sleeve of the needlesforms a catheter capable of being implanted in the tissue.
 12. Theelectric pulse applicator of claim 1, wherein each pulse comprises arectangular pulse having an amplitude of 100 to 1500 V and a pulselength of 10 to 200 microseconds.
 13. The electric pulse applicator ofclaim 12, further comprising a control unit which can produce anelectric pulse sequence to control the selector switch as determined byan operator.
 14. The electric pulse applicator of claim 13, wherein thecontrol unit comprises a program for generating the electric pulsesequence to control the selector switch following the injection of asubstance.
 15. The electric pulse applicator of claim 13, wherein thecontrol unit is also connected to a power supply which is connected tothe pulse generator, the control unit further being connected to anotherswitch which is between the pulse generator and the selector switch. 16.The electric pulse applicator of claim 1, wherein the needles of theelectrodes include hollow passages for allowing an active substance tobe injected locally into the treatment volume.
 17. The electrode pulseapplicator of claim 16, wherein the needles of the electrodes comprisefenestrated needles.
 18. The electric pulse applicator of claim 17,further comprising a needle holder connected to the needles.
 19. Theelectric pulse applicator of claim 17, wherein a needle holder comprisesa holder mechanism allowing the needle holder to carry a syringeassociated with each needle, said syringe being formed of a body and apiston, the piston being connected with the body.
 20. The electric pulseapplicator of claim 19, wherein the holder mechanism includes at leastone plate having openings which allow the needle holder to carry thesyringe.
 21. The electric pulse applicator of claim 19, wherein the bodyof the syringe comprises a hollow body and wherein the piston is fittedinto the hollow body.